1. Field of the Invention
The present invention relates to a sensor device used for measuring the refractive index of a fluid flowing in a channel and detecting a target substance in the fluid.
2. Related Background Art
In recent years, a high-performance biochip and a high-performance sensor using a new technology for analyzing/detecting an organism have been expected as means of realizing a brief home medical examination and proteomics for elucidating the structure and function of protein. For instance, a sensor device using a DNA chip, a DNA microarray, surface plasmon resonance, a multiplex internal reflection method and a photonic crystal has been suggested, researched and developed.
A method for analyzing/detecting an organism using a DNA-microarray makes use of the molecular recognition capacity of a DNA molecule. The DNA microarray has several types of DNA or oligonucleotide arranged on a small carrier such as glass at high density. When a gene is analyzed with the organism-analyzing method, the DNA to be arranged there is cDNA of genetic origin, or the like. As an example, a case of analyzing the gene will be described below. The gene expression is analyzed by the steps of labeling a mRNA or cDNA sample extracted from a specimen with a fluorescent dye; immersing the DNA microarray into a solution containing the labeled sample to make each spot in the DNA microarray emit different fluorescent colors depending on the hybridized ways of a DNA probe with the sample; and analyzing the intensity of the fluorescent signal.
Particularly, a DNA microarray having DNA integrated on the surface of a silicon substrate with the use of photolithography has been called a DNA chip. In a gene analysis using the DNA chip, several types of oligonucleotide are artificially synthesized each in separate micro areas on the surface of a substrate such as glass and a semiconductor. The procedure of the analysis employs hybridization and fluorescent labeling, as in the case of using the DNA microarray. The DNA chip is commercially available under the registered trademark of Gene Chip by Affymetrix Corporation in the United States. Recently, even the DNA microarray prepared by using means such as an ink jet technique other than lithography has been called the DNA chip.
One problem of a procedure using a DNA microarray is to need fluorescent labeling. When the sample is labeled, a procedure of labeling the sample may deteriorate the specificity in DNA hybridization or cause variation in labeling due to variation in the procedure, which may deteriorate the quantitativity of the analysis. Accordingly, the analysis method has not yet been practically used in the true sense in a medical scene. On the other hand, an organism-analyzing/detecting method which does not need fluorescent labeling has been also developed actively. Examples of them are the methods of using the above described surface plasmon resonance, multiple internal reflection method and photonic crystal. The methods all use light for detection.
Generally, a sensor device using light for detection often employs a structure using an interference effect of light. A method for composing the interference sensor device includes a ring type, a Michelson type, a Fabry-Perot type and a Mach-Zehnder type, and they are used in accordance with the purpose.
FIG. 2 shows a schematic block diagram of a Mach-Zehnder interferometer constituted by a Y-branched waveguide formed on a substrate 204. Light 207 emitted from a light source 205 propagates through an optical waveguide 201, and is divided into two light waves at the first Y-branched waveguide 209. The two light waves respectively propagate through the optical waveguide 203 and the optical waveguide 211, and are synthesized into one at the second Y-branched waveguide 210. The synthesized light propagates through the optical waveguide 202, and is emitted from the optical waveguide 202 as light 208. The complex amplitude information of the light 208 is detected in a photo-detecting section 206. If an optical power meter is employed for the photo-detecting section, the intensity of the synthesized light (the intensity of interference light) can be measured with it.
FIG. 3 shows one example of a relationship between a phase difference Δψ between two light waves and the intensity I of interference light, when two light waves having the same angular frequency are synthesized. When each of the two light waves is assumed to have the complex amplitude of A1 cos(ψ1−ωt) and the complex amplitude of A2 cos(ψ2−ωt), I equals (A1+A2)2 when the phase difference Δψ is even-numbered times of π, which is the maximum intensity. On the other hand, when the phase difference Δψ is odd-numbered times of π, I equals (A1−A2)2, which is the minimized intensity.
When the optical path lengths of optical waveguides 203 and 211 are equal, a phase difference becomes 0 and the intensity of interference light is maximized. When an environment in any one of the optical waveguides 203 and 211 changes, and consequently the optical path length changes, the lights having propagated through the optical waveguide 203 and the optical waveguide 211 cause the difference of the phases between them. As a result, the intensity 208 of the interference light changes. By deciding the maximum intensity of the interference light as a reference value and measuring a change in the intensity from the maximum intensity, an amount of change in the environment having occurred in any one of the optical waveguides 203 and 211 can be estimated.
Japanese Patent Application Laid-Open No. 2003-075447 proposes a method for measuring a change of a resonance mode of the photoexcited surface plasmon on a metallic surface with detected light, which is formed due to the coupling of antigen with antibody when the metal surface having the antibody carried thereon contacts with a solution containing the antigen.
A sensor device disclosed in Applied Physics Letters, Vol. 82, No. 26, 30 Jun. 2003, pp. 4648-4650 has a structure of introducing several types of liquids into a micro resonator laser prepared by using a photonic crystal, and measuring the shift of the wavelength of an emitted laser occurring due to a difference of refractive indexes.
When a state of a photonic crystal changes, for instance, a refractive index of a substance constituting the periodic structure of the photonic crystal, or an adsorbed state of another substance to the structure changes, the optical characteristics of the photonic crystal such as a transmission spectrum change. Accordingly, by detecting a change in the optical characteristic of the photonic crystal corresponding with a change in physical quantity such as the concentration of a specified substance in the sample to be detected, the information on the change in the physical quantity of a sample to be detected can be obtained.
When the optical characteristics of the photonic crystal change, incident light onto the photonic crystal is modulated. The modulation includes, for instance, the increase and decrease of the intensity of light, and changes in the phase and the spectral shape of the light. The form of light emitting from the crystal includes transmitted light, luminescent light and reflected light. FIG. 9 diagrammatically shows the state in which a wavelength λ of the light having transmitted through the photonic crystal shifts by Δλ in a spectrum, due to the change of the refractive index of an analyte. Generally, when the refractive index of the photonic crystal increases, the transmission spectrum shifts to a longer side of wavelength. If a quantitative relationship would exist between the amount of the change in the refractive index and the shifted amount of the wavelength, the refractive index can be measured by measuring the transmission spectrum.
A Si (silicon)-two-dimensional photonic crystal can be prepared relatively easily by applying a semiconductor microprocessing technology. FIGS. 1A and 1B show one example of the Si-two-dimensional photonic crystal prepared on a SOI (Silicon On Insulator) substrate. FIG. 1A is a plan view, and FIG. 1B is a sectional view taken in a median line indicated by 1B-1B on FIG. 1A. The Si-two-dimensional photonic crystal has a SiO2 layer 102 formed on a Si substrate 103; a Si layer 101 further formed thereon; and holes 104 hexagonally symmetrically arranged in the Si layer 101. The Si-two-dimensional photonic crystal has a planar shape, is prepared in a plane process, has a micro size, and accordingly is relatively easily merged with a μ-TAS (also called Micro Total Analysis System or Lab on Chip). By the same token, it is easy to form an optical waveguide in a μ-TAS. Accordingly, in an organism-analyzing/detecting method using the μ-TAS, several Si-two-dimensional photonic crystals and several optical waveguides can be used.
However, a conventional sensor device using a photonic crystal has high sensitivity, and accordingly unavoidably sensitively responds to various environmental changes. As a result, the conventional sensor device has had a problem that a signal-to-noise ratio is decreased when there is a signal to be unexpectedly detected, which is not the signal based on the change to be detected and is so-called disturbance. The disturbance is caused by a change of a refractive index occurring due to a temperature change, deformation in the photonic crystal due to an external force and thermal expansion, vibration and the fluctuation of the density of a buffer solution.
For example, disturbance due to a temperature change will be now described. When the temperature of a photonic crystal rises, the shape of the photonic crystal also changes due to thermal expansion, and simultaneously the refractive index changes. The two effects conspire to shift the wavelength of a transmission spectrum to a longer side, along with the increase of the temperature. When expressing an amount of the shift with Δλ2, the total amount of the shift of the transmission spectrum is expressed by Δλ=Δλ1+Δλ2. It is difficult to detect only the shifted amount Δλ1 caused by a change in a refractive index, by extracting it from the total amount, and as a result, the shifted amount Δλ2 lowers the sensitivity of the sensor.